This is a Mentored Clinical Scientist Development Award (K08) application for Robin H. Edwards, M.D.), Associate Member of the Department of Pathology at Fox Chase Cancer Center. It seeks to provide basic research training and career development to support investigation in molecular pathology and a translational infrastructure for the development and validation of new cancer biomarkers. The scientific proposal is focused on understanding the molecular mechanisms of genomic instability in the development and progression of melanoma. Joseph R. Testa, Ph.D., Senior Member and Director of Human Genetics at Fox Chase Cancer Center will serve as primary and basic research mentor. Stuart R. Lessin, M.D., Senior Member and Director of Dermatology at FCCC will serve as co-mentor. The precise etiology of melanoma is unclear; however, genetic factors and response to ultraviolet (UV) irradiation play significant roles. The central hypothesis of this proposal is that alterations in the p16/p14ARF tumor suppressor pathways, and in DNA mismatch repair and nucleotide excision repair (NER) pathways, cooperatively contribute to melanocytic tumor progression by generating genomic instability. The role and stage of involvement of microsatellite instability (MSI) and p16/p14ARF loss will be determined in human melanoma specimens by PCR and IHC methods. Next, three NER genes - XPA, XPC, and XPD - will be analyzed by Western blot and direct sequencing. Finally, the cooperativity of MSI, p16/p14ARF, and the NER genes in generating genomic instability and/or their potential utility as biomarkers of melanocytic progression will be determined through statistical correlations of clinicopathologic parameters. These studies will further our understanding of melanoma pathogenesis and have significance to many cancer models. The Fox Chase Cancer Center provides an outstanding environment for an investigative pathologist to train in the basic sciences and fosters collaborative interactions with a broad spectrum of cancer investigators. This proposal will enable Dr. Edwards to develop into an independent investigator and allow her lab to play a central role in future multi-investigator programs at Fox Chase Cancer Center.